EFFECT OF ANGIOTENSIN II ON INTERLEUKYN-1BETA INDUCED COX-2 AND MPGES-1 EXPRESSION IN PERIVASCULAR FIBROBLASTS: PP.29.141

Abstract

Objective: Adventitial layer plays a critical role in the regulation of vascular function and structure. Angiotensin II has been implicated in the pathophysiological processes that occur in hypertension through its significant proinflamatory actions in the vascular wall, including the production of inflammatory cytokines. Cyclooxygenase-2 (COX-2) and prostaglandin E synthase-1 (mPGES-1) are induced by several proinflammatory agents like cytokines. In this study we have evaluated if angiotensin II alter the effect of interleukin-1β on COX-2 and mPGES-1 expression in cultures of rat aortic fibroblasts. Results and Conclusion: Interleukin-1β (10 ng/ml, 24 h) increased COX-2 and mPGES-1 expression and PGI2 and PGE2 production. Incubation of cells with angiotensin II (0.1 μM, 24 h) modified neither COX-2 and mPGES-1 expression nor prostanoid levels but enhanced COX-2 protein expression, mRNA levels and PGI2 production induced by interleukin-1β; however angiotensin II did not change mPGES-1 protein expression, mRNA levels and PGE2 production induced by interleukin-1β. The potentiator effect of angiotensin II on COX-2 expression was inhibited by the AT1 receptor antagonist losartan. After incubation with interleukin-1β and angiotensin II, p38 and ERK 1/2 MAP kinases phosphorylation was higher and more sustained than in cells only treated with interleukin-1β. The respective inhibitors of p38 and ERK 1/2, PD98059 and SB203580 disminished COX-2 and mPGES-1 protein expression induced by the combination of interleukin-1β plus angiotensin II. Stability of COX-2 mRNA levels was measured in cells incubated with actinomicina D and it was significantly increased in cells stimulated with interleukin-1β plus angiotensin II. These results suggest that angiotensin II participate in the vascular inflamatory response through the increase of cytokine effects on expression of some proinflammatory enzymes such as COX-2, but not mPGES-1. This effect of angiotensin II is thought to be caused by signalling pathways in which p38 and ERK 1/2 MAP kinases are involved.